Article useful for administration of pharmacologically-active substances transdermally, orally, or by means of implant

ABSTRACT

Described is an article of manufacture useful for administration of pharmacologically-active substances, transdermally, orally or by means of subdermal implant comprising a solid vinyl plastisol layer for contacting a patient&#39;s tissue, internally or externally, the layer containing from about 20 up to about 70% by weight of a polyvinyl chloride resin or a polyvinyl chloride-polyvinyl acetate copolymer containing a minor proportion of vinyl acetate; from about 20-70% plasticizer composition, from about 0.5 up to 35% of pharmacologically-active substance such as isosorbide dinitrate, nicotine, clonidine, guanfacine, indomethacin, glyceryl trinitrate and prostaglandin and optionally excipients. Also described is the novel plasticizer-polyvinyl chloride composition of matter comprising 1-dodecylhexahydro-2H-azepin-2-one and polyvinyl chloride resin taken together with a pharmacologically-active substance .[.whereint he.]. .Iadd.wherein the .Iaddend.1-dodecylhexahydro-2H-azepin-2-one not only acts as a plasticizer but also acts as a penetration enhancer (through tissue) for the pharmacologically-active substance.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates broadly to articles of manufacture foradministration of pharmacologically-active substances, transdermally,orally and by means of implant (e.g., subdermal implant). The devicesconsist essentially of a vinyl chloride polymer or copolymer of vinylchloride containing a majority of vinyl chloride monomeric units and asmall amount of other vinyl monomeric units, e.g., vinyl acetate, andintimately dispersed therewith at least one of saidpharmacologically-active agents and a plasticizer. Examples ofpharmacologically-active agents are isosorbide dinitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin. Contemplated within the scope of this invention aredevices for the controlled release and transdermal administration ofsuch pharmacologically-active agents as nitroglycerine (e.g. in thetreatment of conditions, e.g., angina pectoris).

2. The Prior Art

Many prior art articles of manufacture have been disclosed forcontrolled release delivery of various drugs including transdermaldelivery of nitroglycerin. In general, however, available commercialdevices and indeed devices published in the prior art are limited withrespect to rate of delivery of pharmacologically-active substance.

Canadian Pat. No. 930,668 discloses a bandage for administering drugscomprised of a backing member, a pressure sensitive adhesive, and atleast one reservoir disposed between the backing member and pressuresensitive adhesive. The reservoir is comprised of a systemically activedrug formulation confined within a wall member, the wall member beingformed from a drug release rate controlling material. The reservoir canbe in the form of discrete microcapsules or distinct reservoircompartments or layers. The reservoir can also be in the form of walledcontainers having one or more interior drug-containing chambers, as wellas solid matrixes having a systemically active drug distributedtherethrough. The Canadian patent discloses a wide variety of materialswhich can be used to form the reservoir. Among the materials mentionedare silicone rubbers, hydrophilic polymers of monoesters of an olefinicacid, polyvinylalcohol, polyvinylacetate, plasticized polyvinylchloride,plasticized nylon, collagen, modified collagen, gelatin, and waxes suchas polyethylene wax, oxidized polyethylene wax, hydrogenated castor oiland the like, with the silicone rubbers being preferred. The Canadianpatent does to contain any examples showing the use of plasticizedpolyvinyl chloride, and does not show the use of a PVC plastisol.

Similarly, Zaffaroni, U.S. Pat. No. 3,921,636 issued on Nov. 25, 1975discloses a drug delivery device for administering a drug at acontrolled rate for a prolonged period of time comprising a plurality ofreservoirs containing drug distributed through a matrix. The reservoirsand the matrix are formed of materials permeable to passage of the drug.The rate of drug permeation from the reservoir is lower than the rate ofpermeation through the matrix so that release from the reservoir is thedrug release rate controlling step. Thus, Example 6, at column 15, lines5-30 of U.S. Pat. No. 3,921,636 relates to a polyvinyl chloride resincontaining plasticizer and prednisolone disodium phosphate thusly:

"A drug delivery device for the controlled, oral administration ofwater-soluble prednisolone is prepared as follows: first, a plurality ofdrug reservoirs comprising porous, discrete particles of polymerizedpoly(vinyl chloride) of about 100 microns diameter are prepared bymixing 100 g of suspension grade poly(vinyl chloride) resin with 50 g ofoctyl diphenyl phosphate and 10 g of predinisolone disodium phosphate atroom temperature into a sticky, wet mass. Next, the temperature of themixture is raised to 80° C. for about 3 to 7 minutes, while stirring, toform dry, free flowing, discrete drug reservoirs. The reservoirs areuniformly dispersed through a matrix by mixing 50 g of reservoirscontaining the prednisolone with 140 g of polydimethylsiloxane, 10 g ofsilicone oil, and 0.5 g of stannous octoate. After mixing theingredients, the mixture is charged into pill molds and allowed to curefor 30 minutes. Oral administration of the resulting device yields acontrolled essentially constant rate of release of prednisolonephosphate to the gastrointenstinal tract to give a more uniform bloodlevel of premisolone over a longer period of time than is achieved whenprednisolone alcohol is administered by standard prior art pills."

Furthermore, as is well known, polyvinyl chloride (PVC) is never usedalone, but is always mixed with other ingredients before beingprocessed. Polyvinyl chloride appeared initially to be an unpromisingresin because of its thermal instability and high rigidity. PVC,however, was then discovered to form a rubber-like material whendissolved hot in high boiling solvents known as plasticizers and cooledto room temperature. PVC is now available in a number of differentphysical forms and types, and its manufacture depends on the formdesired. Thus, PVC is available as a vinyl latex, a dispersion resin, ora general purpose resin. PVC latexes are true colloidal dispersions ofsubmicrometer particles in water, stabilized by a surfactant system, andneed plasticizers in order to form a continuous film. The PVC in vinyllatex is manufactured by emulsion polymerization.

Dispersion resins are produced by emulsion polymerization and are mixedwith plasticizers to form a colloidal dispersion. Such dispersions areknown as plastisols and are easily handled and readily pourable. Whenheated to a temperature of about 148° to 177° C., the plastisol istransformed to a homogeneous melt which, upon cooling to below 50° C.,results in a tough flexible product. The PVC resins made by emulsionpolymerization are hard spheres of particle size between about 0.05 and20 microns, such as between 1 and 20 microns. They do not have theability to absorb plasticizers. Therefore, a mixture containing, forexmaple, 30% plasticizer and 70 PVC resin, produces a flowable liquid,known a plastisol.

General purpose PVC resins are made by mass and suspensin polymerizationprocess, and comprise the largest amount of PVC resins produced, such asat least 80% of all PVC resins, and are used chiefly to make so-called100% vinyl products by a variety of molding and extrusion techniques.Resins intended for flexible applications should have good uptake ofplasticizer in a dry blending operation and contain more than 25% of aplasticizer system. PVC compounds that contain less than 25%plasticizers are referred to as semirigid compounds: The PVC resinsmanufactured by suspension and bulk polymerization are 50 to 200, suchas 100 to 150 microns in diameter, and are like sponges They are capableof absorbing large amounts of plasticizers, so that even 50%plasticizer, 50% PVC resin composition would result in a non-flowing,solid material.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an article ofmanufacture which offers enhanced delivery capability ofpharmacologically-active agents over prior commercial devices(transdermal devices, articles used to orally administerpharmacologically-active agents and subdermal implants used toadminister subdermally pharmacologically-active agents) by providing anarticle capable of efficaciously administering pharmacologically-activeagents such as isosorbide dinitrate, nicotine, indomethacin, clonidine,glyceryl trinitrate, guanfacine, and prostaglandin directly from aplastisol resin layer in which the pharmacologically-active agent isincorporated in relatively high concentrations, e.g , from 0.5 up to35%.

This invention also enables the administration of apharmacologically-active agent, such as isosorbide dimitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine, andprostaglandin to be achieved through an article of manufacture, e.g., atransdermal delivery device requiring contact with a relatively smallerarea of a patient's tissue, such as the epidermis in the case of atransdermal delivery device.

Thus, this invention is directed to an article of manufactureincorporating a polyvinyl chloride resin plastisol monolayer foradministration of pharmacologically-active agents transdermally, orallyor by means of subdermal implant to a patient requiring treatment for acondition such as, for example, angina pectoris (in the case of the useof such materials as nitroglycerin). In particular, it has been foundthat pharmacologically-active agents such as isosorbide dinitrate,nicontine, indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin can be homogeneously dispersed in high concentrations in aplastisol of an emulsion polymerized polyvinyl chloride resin andplasticizer; the composition is fused into a solid layer and the layeris applied onto the tissue of a patient (either transdermally, orally orsubdermally) whereby the pharmacologically-active agent is absorbedeither (i) through the patient's skin or (ii) through the patient'sinternal membranes or (iii) directly ionto the circulation system.

A preferred embodiment comprises a multilayer adhesive bandage deviceincorporating a plastisol monolayer containing homogeneously dispoersedpharmacologically-active agents, e.g., isosorbide dinitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a preferred pharmacologically-activeagent delivery device in accordance with this invention.

FIG. 2 is a plan view of a strip of material in accordance with thisinvention viewed from the surface which is applied to the patient'sskin.

FIG. 3 is a plan view of material in accordance with this inventionviewed from the surface away from the surface which is applied to thepatient's skin.

FIG. 4 is an enlarged sectional schematic view of a specific embodimentof the invention; a transdermal device for controlled release of apharmacologically-active agent from a plastisol monolayer through amembrane transdermally.

FIG. 5 is an enlarged sectional schematic view of another embodiment ofthe invention where there is no membrane separating the plastisolmonolayer from the epidermis and whereby pharmacologically-active agentis transported from the plastisol transdermally into the patient.

FIG. 6 is a perspective view of a roll of material in accordance withthis invention.

FIG. 7 is a graph of tensile strength (PSI) versus percent resincontaining either of isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate or guanfacine, specifically as describedherein in the description of Examples VIII-XIII, infra.

FIG. 8 is graph showing release rate of pharmacologically-active agent(in micrograms per square centimeter per hour) versus percent resin,individually, for isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate or guanfacine specifically inrelationship to Examples XIV-XIX, infra.

FIG. 9 is a graph of plasma concentration (picograms per milliliter)versus time detected in a human subject during the clinical studyconcerning the composition of matter consisting of polyvinyl chlorideresin, dioctyl adipate plasticizer and prostaglandin as specifically setforth in Example XX, infra.

FIG. 10 is a graph showing the effective decrease in diastolic bloodpressure of the human subject observed during the period of patchapplication as specifically set forth in Example XX.

FIG. 11 is a graph of delivery of nitroglycerine versus time resultingfrom the use of the formulation of Example XXI.

FIG. 12 is the infrared spectrum of ADMEX® 760 as used in ExamplesII-XIX.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein with respect to preferred embodimentsincluding transdermal devices containing variouspharmacologically-active agents including, but not limited to,indomethacin having the structure: ##STR1## guanfacine having thestructure: ##STR2## clonidine having the structure: ##STR3## nicotinehaving the structure: ##STR4## isosorbide dinitrate having thestructure: ##STR5## glyceryl trinitrate and prostaglandin (e.g., methyl(±) -[11a, 5z and 5E), 13E, 16R (and 16S)]-16-ethenyl-11,16dihydroxy-9-oxoprosta-5, 13-dien-1-oate. It will be understood thatother embodiments may be employed within the spirit and scope of thisinvention.

The articles of our invention are useful for transdermal, oral andsubdermal administration of pharmacologically-active substances andcomprise a solid vinyl plastisol layer (consisting essentially ofpolyvinyl chloride and a plasticizer) for contacting a patient's skin orother membrane. The vinyl plastisol layer contains from about 20 up toabout 70% by weight of a polyvinyl chloride resin which consistsessentially of a vinyl chloride polymer containing, predominantly orcompletely repeating vinyl chloride monomeric units and in an amount ofless than about 10% other repeating vinyl units, e.g., repeating vinylacetate units; from about 20% up to about 70% by weight of thecomposition of one or more plasticizers; from about 0.5 up to about 35%by weight of the total composition of a pharmacologically-activesubstance, such as isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate, guanfacine or prostaglandin andoptionally other excipients, such as materials which will acceleratetransdermal penetration as exemplified hereinafter. .Iadd.As one exampleof the use of a pharmacologically-active substance, nitroglycerin can bepresent in an amount of about 20-35%. .Iaddend.

It has now been found that the release rate of an active agent, which isuniformly dispersed in the vinyl plastisol layer, is criticallydependent upon the proportion of the PVC resin in the composition; andthe release follows a bell shaped curve (FIG. 8), the maximum occurringin the range of 30 to 50% PVC content. This is an unexpected finding,which has not hitherto been known. Such a release behavior permitstailoring of release rates of an agent from the matrix.

The reservoir layers of this invention are relatively weak and less than1500 psi, (FIG. 7), highly flexible and soft materials. In contrast, theflexible vinyl films of commerce are considerably stronger materialsexhibiting tensile strengths of the order of 1,500 to 5,000 psi. Thepolyvinyl chloride resin content of the commercially useful andavailable flexible vinyl films ranges from 50 to 75%. Such materials donot have adequate drug permeating characteristics to serve as suitabledrug delivery reservoirs.

Referring to FIG. 1, the device 1 includes a solid plastisol monolayer 2which is composed of or comprises resin, plasticizer and apharmacologically-active agent as set forth supra.

A formulation for layer 2 may comprise from about .[.2.]. .Iadd.20.Iaddend.up to about 70% by weight of the vinyl resin, from about 20 upto about 70% by weight of plasticizer composition, from about 0.5 up toabout 35% by weight of pharmacologically-active agent and the remainderbeing other excipients, such as materials which will enhance skinpenetration. We have found that the substance1-dodecylhexahydro-2H-azepin-2-one (also known as AZONE® having thestructure: ##STR6## acts as both a plasticizer and as an agent whichenhances transdermal penetration of pharmacologically-active agents suchas isosorbide dinitrate, indomethacin and the like as set forth supra.By the same token, N,N-diethyltoluamide having the structure: ##STR7##acts in the same manner as AZONE®.

Thus, for example, for a device suitable in the treatment of anginapectoris, a specific formulation for layer 2 comprises about 54%polyvinyl chloride (PVC) resin, about 36% dioctyl phthalate (DOP)plasticizer and 10% nitroglycerin. To prepare layer 2, the PVC and DOPare first blended. Due to the explosive character of the drug,dispersion of the nitroglycerin into the resulting PVC/plasticizersplastisol is then carried out under controlled conditions.

The articles of the present invention including the transdermal devicesas well as subdermal implants and orally ingested articles of thepresent invention comprise a polyvinyl chloride plastisol layer in afused state and a pharmacologically-active agent uniformly dispersed inthe fused layer which may be referred to as a reservoir for thepharmacologically-active agent. The polyvinyl chloride reservoir in thereset invention is prepared from polyvinyl chloride resin and a primaryplasticizer for the resin.

The polyvinyl chloride resin employed in the practice of the presentinvention is that which is specifically used in preparing PVCplastisols, namely, PVC resins which are made by the well known emulsionpolymerization process, which are hard spheres of particle size between0.05 and 20 microns, such as between 1 and 20 microns, for example,between 1 and 5 microns, or between 0.05 and 1 micron, and which do nothave the ability to absorb plasticizers to any great extent. Instead,the plasticizer wets the resin particles at room temperature and onlythen very slowly penetrates and solvates the resin. These PVC resinswhen mixed with plasticizers, such as a mixture of 30% primaryplasticizer, 70% PVC resin, give a flowable liquid known as plastisolwhich can then be fused at, for example, approximately 250° F. forapproximately 30 seconds to provide a solid polymer layers. The PVCresin employed in the present invention is in contrast to the generalpurpose PVC resins which are produced by suspension or bulkpolymerization and which are used in calendering and extrusionprocesses, which are 50 to 200 microns, such as 100 to 150 microns indiameter, and are like sponges. Thus, the genial purpose resins arecapable of absorbing large amounts of plasticizers so that even a 50%DOP and 50% PVC resin would result in a non-flowing solid material. Themolecular weight of the PVC resins employed in the present inventionpreferably is a weight average molecular weight between 80,000 and250,000, such as a weight average molecular weight of 123,000. Asuitable polyvinyl chloride resin is one sold by Occidental Chemical Co.under the designation FPC 6338 containing about 96% vinyl chloridemonomer units of about 4% vinyl acetate monomer units. Thus, thepolyvinyl chloride resin can be a copolymer containing preferably atleast 90% by weight vinyl chloride monomer units, such as a copolymerbased on vinyl chloride and vinyl acetate.

The polyvinyl chloride resin generally is present in the layer in anamount of 10 to 75 weight percent, preferably 20 to 70 weight percent,based on the total weight of the vinyl plastisol composition.

The primary plasticizer which is employed in the present invention canbe dioctylphthalate (DOP), benzylbutylphthalate,tri-2-ethylhexylmalaete, dioctyl adipate, epoxidized soybean oil,polymeric adipate plasticizers, which are polymers of adipic acid with amonomer, such as propylene plycol, and for example can be obtained underthe designation Drapex 334F from Witco Chemical Corp., or any otherknown primary plasticizer for PVC which is biologically acceptable.

The other examples of polyester adipates, glutarates and sebacates are:

polyester adipate (P)P-644;

polyester glutarate (P)P-530;

polyester glutarate (P)P540;

polyester glutarate (P)P-550;

polyester glutarate (P)P-7035;

polyester glutarate (P)P-7035M;

polyester glutarate (P)P-7046;

polyester glutarate (P)P-7092; and

polyester sebacate (P)P-1070

manufactured by the C. P. Hall Co., 7300 S. Central Avenue, Chicago,Ill. 60638. Other preferred plasticizers are those which are known as"phthalate" plasticizers, for example, ADMEX® 760 which is a highmolecular weight (MW=8000) phthalte plasticizer manufactured by theSherex Division of Nuodex Inc. In general, polyester plasticizers whichare polyesters of (i) 1,4-terephthalic acid and/or 1,2-phthalic acidwith (ii) ethylene glycol or 1,3-propylene glycol having molecularweights in the range of 4000-10,000 are preferred.

Another preferred plasticizer which also acts as a skin penetratingenhancer for pharmacologically-active drugs which are intended fortransdermal delivery from devices such as those set forth in FIGS. 1, 5and 6 is the compound having the structure: ##STR8## known as AZONE®marketed by the Nelson Research and Development Co. The compositioncomprising PVC and the compound having the structure: ##STR9## is anovel composition of matter.

Mixtures of known plasticizers can be used. The term "primaryplasticizer" as used herein refers to a plasticizer which can be usedalone to effect plasticization and is highly compatible with PVC at highconcentrations, such as, for example, 150 parts per hundred. Primaryplasticizers are contrasted with "secondary plasticizers" which, becauseof limited compatibility with PVC, cannot be used alone. See,Kirk-Othmer Encyclopedia of Chemical Technology, Volume 23, 3rd Edition,especially pages 913 and 914 for a discussion of primary and secondaryplasticizers, which is incorporated by reference herein.

The primary plasticizer generally is present in an amount of 20 to 85weight percent, preferably 20 to 70% based on the total weight of thevinyl plastisol layer.

The PVC plastisol may optionally contain other additives or "excipients"useful in the practice of this invention, for example, material whichenhance skin penetrated of the pharmacologically-active substances(e.g., 1,6-hexanediol and n-decyloleate) and thickeners, e.g., silica(preferably "fumed" silica, for example, AEROSIL® in an amount of from1-6% of the layer).

With reference to FIG. 1, the blended plastisol containing for example,PVC, DOP and nitroglycerin is then coated at a rate of about 36ounces/yd² on a backing, and then fused into solid plastisol layer 2.The backing may be a single layer of drug impermeable plastic or othermaterial, but is preferably composed of two layers 3 and 4. Layer 3 maybe MYLAR® (polyester produced from ethylene glycol and phthalicanhydride) about 0.5 mils thick, and layer 4 may be PVC, about 4 milsthick. The backing 3,4 substantially blocks loss of drug from theplastisol layer 2other than in the direction of the surface which, inuse, will contact the patient's skin.

The blended plastisol which is coated on the backing can be fused into ahomogeneous solid by heating it for a short period, such as 15 to 30seconds, at a temperature of, for example, 250° to 280° F. The use of aplastisol to form solid layer 2 enables to be formed by using a lowtemperature for a short period of time and provides conditions which donot affect the stability of the pharmacologically-active agents.

A strip of solid plastisol layer 2 and backing 3,4 is then tonded to apressure-sensitive adhesive layer 5 which in turn is provided with anon-adhesive backing 6 such as one made of plastic, moisture-prooffabric, aluminum foil, etc.

When not in use, the entire surface intended for skin contact ispreferably covered with a release paper 7 or the like which is removedto expose surfaces of the adhesive layer 5 and drug containing plastisollayer 2 for application to the patient's skin.

FIG. 2 shows a plan view of a strip of material 20 during the stage ofmanufacture at which a strip of the plastisol 2 (backing 3,4 not shown)has been applied to the adhesive tape (backing 6 not shown). For thepreferred device for the controlled administration ofpharmacologically-active agent e.g., indomethacin, isosorbide dinitrate,nicotine, clonidine, glyceryl trinitrate, guanfacine or prostaglandin, aplastisol strip preferably about one inch (1") in width is applied on atwo and one-half inch (21/2") wide pressure-sensitive adhesive strip.

FIG. 3 shows a plan view of a strip of the material 30 in accordancewith this invention; spaced lines 31 may be embossed or printed on thesurface away from skin contact so that the patient may convenientlymeasure out and cut off the proper amount of tape device to provide theprescribed daily dosage. For a device for administering thepharmacologically-active agent, e.g., nitroglycerin, for example asegment 1" long cut from the longer tape (resulting in an approximatelyone square inch (1 sq. in.) of active surface against the the patient'sskin) will provide a dosage of about 17 mg/24 hours; this is to be anenhanced rate of delivery compared with commercially availabletransdermal drug delivery devices and also will provide the patient witha bandage device having a surface area much smaller than found inpreviously available devices.

Referring to FIG. 4, the components of embodiment 33 are backing layer34, a reservoir layer 35 that contains supplies of percutaneousabsorption enhancer and pharmacologically-active substance, such asindomethacin, a diffusion membrane layer 36 and a peripheral ring 37 ofcontact adhesive. The diffusion membrane layer may be composed of apolymer, such as copolymer of ethylene and methyl acrylate with themethyl acrylate being in the range of 2-90% by weight of the polymer, orblends of such copolymer with low density polyethylene, high densitypolyethylene or linear low density polyethylene. The contact adhesivecomponent of embodiment 33 is in the form of a peripheral ring.Optionally, backing layer 34 may also be a semi-permeable membrane.Neither the pharmacologically-active agent, e.g., isosorbide dinitratenor enhancer passes through ring 37 and it therefore need not bepermeable to those compositions. Optionally, the contact adhesive may beattached directly to the membrane 36, in which case the adhesive isselected so that it is permeable to the active agent. Secondly, thebasil surface from which the pharmacologically-active substance andenhancer (e.g., AZONE® is transferred to the skin is defined bydiffusion membrane layer 36. The backing layer is not flat but insteadforms a pocket or cavity in which the reservoir layer is held. The outeredge of the backing layer is sealed to the peripheral ring of thecontact adhesive as more specifically set forth in U.S. Pat No.4,379,454 issued on Apr. 12, 1983, the disclosure of which isincorporated herein by reference. Similarly, an article within thecontemplation of our invention need not have a matrix as illustrated inFIG. 5 wherein the backing 61 totally surrounds thePVC-plastisol-plasticizer matrix 62 and is firmly in place as with anadhesive on the skin 63.

As shown in FIG. 6, the device of the invention may conveniently beprovided in the form of a tape roll 50 from which daily dosagerequirements may be clipped by the patient.

The device is capable of application to humans or other animals capableof usefully absorbing drugs through the skin.

Other embodiments of our invention are those useful in, for example,U.S. Pat. Nos. 4,573,996 and 4,573,995 issued on Mar. 4, 1986, thespecifications for which are incorporated by reference herein.

EXAMPLE I

A plastisol was formed by mixing 54% of a polyvinyl chloride resin soldunder the designation FPC 6338 by Occidental Chemical Corp. and having aparticle size between 1 and 5 microns, 36% DPO, and 10% nitroglycerin.The product was coated onto 1 mil polyester (MYLAR) film and cured at280° F. The final product consisted of 8.8% nitroglycerin, 31.8% DOP,47.8% FPC 6338, 11.6% polyester. This product can be used for deliveryof nitroglycerin percutaneously.

EXAMPLES II-XIX FUSED PLASTISOL DRUG RESERVOIR EXAMPLES

Fused plastisol drug reservoirs having variable PVC: plasticizer ratioswere prepared by heating cast films of the drug containing plastisols at290° F. for 60 seconds. The drugs used were isosorbide dinitrate (ISDN)and nicotine. AZONE® having the structure: ##STR10## (registeredtrademark of the Nelson Research and Development Co.) and ADMEX® 760(which is a high molecular weight (MW=8000) phthalate plasticizermanufactured by the Sherex Division of Nuodex Inc.) were used as primaryplasticizers in the case of the ISDN and the nicotine reservoirs,respectively. The films, thus prepared, were optically transparent. FIG.12 is the infrared spectrum ADMEX® of 760.

The stress-strain properties of the films were determined employingstandard procedures using Instron Universal Testing Instrument. Theability of the reservoir to release the drug evaluated by measuring thedissololution rate of the drug in fluid medium (receptor phase) when aknown surface area of drug reservoir film was exposed to an excess ofthe receptor at 31° C. The dissolution rate studies were conducted aFranz diffusion cell. The receptor phase for the nicotine study was pH4.0 citric acid buffer solution (an aqueous solution containing 1.2%citric acid and 1.1% disodium hydrogen phosphate), and that for the ISDNstudy was an aqueous solution containing 20% polyethylene glycol 400.The dissolution rate of the drug was calculated from the change inconcentration of the drug in the receptor phase at different timeintervals. The nicotine and ISDN concentrations were determined byultraviolet spectroscopy and high pressure liquid chromatographicprocedures, respectively.

EXAMPLES II-VII

In the following formulations .[.(A-F.]. (.Iadd.A-E .Iaddend.in each ofExamples II-VII), the following terms having the following meanings asnow given:

    ______________________________________                                        ISDN:      Isosorbide dinitrate having the structure:                                     ##STR11##                                                         AZONE:     The compound having the structure:                                             ##STR12##                                                         6338:      A vinyl chloride acetate copolymer                                            having a vinyl acetate content of 4.0-4.5%                                    manufactured by the Occidental Chemical                                       Corporation.                                                       ADMEX:     A high molecular weight                                                       (MW = 8000) phthalate                                                         plasticizer manufactured by the Sherex                                        Division of Nuodex Inc.                                            Nicotine:  The compound having the structure:                                             ##STR13##                                                         Indomethacin:                                                                            The compound having the structure:                                             ##STR14##                                                         Clonidine: The compound having the structure:                                             ##STR15##                                                         GTN:       Glyceryl trinitrate.                                               Guan.:     Guanfacine having the structure:                                               ##STR16##                                                         DOP:       Dioctyl phthalate.                                                 HG:        1,6-Hexylene glycol.                                               Cer 140:   "Ceraphyl 140" being n-decyl oleate.                               ______________________________________                                    

EXAMPLE II

    ______________________________________                                        ISDN FORMULATIONS                                                             "A"          "B"      "C"      "D"    "E"                                     ______________________________________                                        ISDN    15.0%    15.0%    15.0%  15.0%  15.0%                                 AZONE   59.5%    51.0%    42.5%  34.0%  25.5%                                 6338    25.5%    34.0%    42.5%  51.0%  59.5%                                 ______________________________________                                    

EXAMPLE III

    ______________________________________                                        NICOTINE FORMULATIONS                                                         "A"          "B"      "C"      "D"    "E"                                     ______________________________________                                        Nicotine                                                                              30.0%    30.0%    30.0%  30.0%  30.0%                                 ADMEX   49.0%    42.0%    35.0%  28.0%  21.0%                                 6338    21.0%    28.0%    35.0%  42.0%  49.0%                                 ______________________________________                                    

EXAMPLE IV

    ______________________________________                                        INDOMETHACIN FORMULATIONS                                                            "A"   "B"      "C"      "D"    "E"                                     ______________________________________                                        Indomethacin                                                                           15.0%   15.0%    15.0%  15.0%  15.0%                                 AZONE    25.5%   34.0%    42.5%  51.0%  55.0%                                 6338     59.5%   51.0%    42.5%  34.0%  30.0%                                 ______________________________________                                    

EXAMPLE V

    ______________________________________                                        CLONIDINE FORMULATIONS                                                        "A"          "B"      "C"      "D"    "E"                                     ______________________________________                                        Clonidine                                                                             20.0%    20.0%    20.0%  20.0%  20.0%                                 ADMEX   60.0%    55.0%    50.0%  45.0%  41.0%                                 6338    20.0%    25.0%    30.0%  35.0%  44.0%                                 ______________________________________                                    

EXAMPLE VI

    ______________________________________                                        GTN FORMULATIONS                                                              "A"          "B"      "C"      "D"    "E"                                     ______________________________________                                        GTN      8.0%     8.0%     8.0%   8.0%   8.0%                                 ADMEX   62.0%    53.0%    46.0%  39.0%  32.0%                                 6338    30.0%    39.0%    46.0%  53.0%  60.0%                                 ______________________________________                                    

EXAMPLE VII

    ______________________________________                                        GUANFACINE FORMULATIONS                                                       "A"          "B"      "C"      "D"    "E"                                     ______________________________________                                        Guan,   30.0%    30.0%    30.0%  30.0%  30.0%                                 DOP     25.0%    21.0%    18.0%  14.0%  10.0%                                 HG      12.5%    12.5%    12.5%  12.5%  12.5%                                 Cer 140 12.5%    12.5%    12.5%  12.5%  12.5%                                 6338    20.0%    24.0%    27.0%  31.0%  35.0%                                 ______________________________________                                         NOTE:                                                                         The hexylene glycol enhances the permeability transdermally of the            guanfacine. The Cer 140 adjusts the activity of the guanfacine in the         reservoir.                                                               

EXAMPLES VIII-XIII

In the following examples, the following terms have meanings as givenherein:

    ______________________________________                                        ISDN:      Isosorbide dinitrate having the structure:                                     ##STR17##                                                         Nicotine:  The compound having the structure:                                             ##STR18##                                                         Indomethacin:                                                                            The compound having the structure:                                             ##STR19##                                                         Clonidine: The compound having the structure:                                             ##STR20##                                                         GTN:       Glyceryl trinitrate.                                               Guan.:     Guanfacine having the structure:                                               ##STR21##                                                         ______________________________________                                    

FIG. 7 shows tensile versus percent resin for each of the aboveformulations. The curve indicated by reference numeral 70 is the curvefor clonidine. The curve indicated by reference numeral 71 is the curvefor guanfacine. The curve indicated by reference numeral 72 is the curvefor .[.indocin.]. .Iadd.indomethacin.Iaddend.. The curve indicated byreference numeral 73 is the curve for nicotine. The curve indicated byreference numeral 74 is the curve for isosorbide dinitrate. The curveindicated by reference numeral 75 is the curve for glyceryl trinitrate.

EXAMPLE VIII

    ______________________________________                                        ISDN                                                                          % Resin      Tensile Strength                                                 ______________________________________                                        25.5          57.21                                                           34.0         144.09                                                           42.5         399.54                                                           51.0         663.81                                                           59.5         1077.53                                                          ______________________________________                                    

EXAMPLE IX

    ______________________________________                                        NICOTINE                                                                      % Resin      Tensile Strength                                                 ______________________________________                                        21.0          54.22                                                           28.0         125.51                                                           35.0         204.39                                                           42.0         300.57                                                           49.0         671.30                                                           ______________________________________                                    

EXAMPLE X

    ______________________________________                                        INDOMETHACIN                                                                  % Resin      Tensile Strength                                                 ______________________________________                                        30.0          99.63                                                           34.0         162.00                                                           42.5         495.00                                                           51.0         764.00                                                           59.5         1447.00                                                          ______________________________________                                    

EXAMPLE XI

    ______________________________________                                        CLONIDINE                                                                     % Resin      Tensile Strength                                                 ______________________________________                                        20.0         118.36                                                           25.0         228.70                                                           30.0         308.99                                                           35.0         487.65                                                           44.0         440.16                                                           ______________________________________                                    

EXAMPLE XII

    ______________________________________                                        GTN                                                                           % Resin      Tensile Strength                                                 ______________________________________                                        30.0          17.53                                                           39.0          74.90                                                           46.0         116.43                                                           53.0         738.85                                                           60.0         1339.02                                                          ______________________________________                                    

EXAMPLE XIII

    ______________________________________                                        GUAN                                                                          % Resin      Tensile Strength                                                 ______________________________________                                        20.0          84.83                                                           24.0         128.40                                                           27.0         180.50                                                           31.0         131.50                                                           35.0         203.21                                                           ______________________________________                                    

EXAMPLES XIV-XIX

In the following examples, the following terms have meanins as set forthbelow:

    ______________________________________                                        ISDN:      Isosorbide dinitrate having the structure:                                     ##STR22##                                                         Nicotine:  The compound having the structure:                                             ##STR23##                                                         Indomethacin:                                                                            The compound having the structure:                                             ##STR24##                                                         Clonidine: The compound having the structure:                                             ##STR25##                                                         GTN:       Glyceryl trinitrate.                                               Guan.:     Guanfacine having the structure:                                               ##STR26##                                                         ______________________________________                                    

EXAMPLE XIV

    ______________________________________                                        ISDN                                                                                 % Resin                                                                              Release                                                         ______________________________________                                               25.5   91.66                                                                  34.0   108.90                                                                 42.5   93.50                                                                  51.0   65.71                                                                  59.5   50.29                                                           ______________________________________                                    

EXAMPLE XV

    ______________________________________                                        NICOTINE                                                                             % Resin                                                                              Release                                                         ______________________________________                                               21.0    40.76                                                                 28.0   122.78                                                                 35.0   218.25                                                                 42.0   243.55                                                                 49.0   216.18                                                          ______________________________________                                    

EXAMPLE XVI

    ______________________________________                                        INDOMETHACIN                                                                         % Resin                                                                              Release                                                         ______________________________________                                               30.0   36.14                                                                  34.0   87.01                                                                  42.5   68.75                                                                  51.0   24.49                                                                  59.5    8.65                                                           ______________________________________                                    

EXAMPLE XVII

    ______________________________________                                        CLONIDINE                                                                            % Resin                                                                              Release                                                         ______________________________________                                               20.0   103.67                                                                 25.0   108.22                                                                 30.0   80.85                                                                  35.0   82.18                                                                  44.0   62.81                                                           ______________________________________                                    

EXAMPLE XVIII

    ______________________________________                                        GTN                                                                                  % Resin                                                                              Release                                                         ______________________________________                                               30.0   41.91                                                                  39.0   48.54                                                                  46.0   42.63                                                                  53.0   46.02                                                                  60.0   35.81                                                           ______________________________________                                    

EXAMPLE XIX

    ______________________________________                                        GUAN                                                                                 % Resin                                                                              Release                                                         ______________________________________                                               20.0   31.72                                                                  24.0   56.85                                                                  27.0   63.06                                                                  31.0   88.41                                                                  35.0   165.82                                                          ______________________________________                                    

FIG. 8 is a graph showing release rate in micrograms per squarecentimeter per hour versus percent resin. The curve indicated byreference numeral 80 is the curve for nicotine. The curve indicated byreference numeral 81 is the curve for clonidine. The curve indicated byreference numeral 82 is the curve for guanfacine. The curve indicated byreference numeral 83 is the curve for isosorbide dinitrate. The curveindicated by reference numeral 84 is the curve for indomethacin. Thecurve indicated by reference numeral 85 is the curve for glyceryltrinitrate.

EXAMPLE XX Transdermal Delivery of Prostaglandin from Drug ReservoirHuman Clinical Study

I Drug: Prostaglandin (American Cyanamid Co.) Methyl (±)-[11α, 5z (and5E), 13E, 16R (and 16S)]ethenyl-11,16-dihydroxy-9-oxoprosta-5,13-dien-11-oate (an analog of Prostaglandin E₂).

II. Pharmacological Activity: Antihypertensive

III. Patch Formula:

    ______________________________________                                        PVC Resin         59.7%                                                       Dioctyl Adipate   38.2%                                                       50% Prostaglandin  2.1%                                                       in Dioctyl Adipate                                                            ______________________________________                                    

IV. Results:

A. The Drug Concentration up to 500 pg/ml was detected in a humansubject. (FIG. 9).

B. Effective decrease in diastolic blood pressure of the human subjectwas observed during the period of patch application (FIG. 10).

The curve indicated by reference numeral 90 shows plasma concentrationin picograms per ml versus time in hours. The curve indicated in FIG. 10by reference numeral 101 shows mean decrease in sitting diastolic bloodpressure following administration of the subject patch formula to normalsubjects in a cross over study (sample size=15). The units of pressureare mmHg and the units of time are in hours.

EXAMPLE XXI Transdermal Delivery of Nitroglycerin from DrugReservoir-Human Clinical Study

Drug: Nitroglycerin (Glyceryl trinitrate)

Pharmacological Activity: Vasodilator

Patch Formulation:

    ______________________________________                                        Ingredient         Percentage                                                 ______________________________________                                        Nitroglycerin      9.6%                                                       Dioctyl Phthalate  76.8%                                                      PVC Resin          9.6%                                                       Aerosil (Fumed Silica)                                                                           4.0%                                                       ______________________________________                                    

Results

The patch delivered adequate nitroglycerin through skin of humansubjects to provide a concentration of 0.1 to 0.2 ng/ml in the bloodplasma for a period of 3 days as set forth in FIG. 11. The graphindicated by reference numeral 111 is a graph of delivery of glyceryltrinitrate in nanograms/ml versus time (in hours).

EXAMPLE XXII

In Vivo Transdermal Delivery of Isosorbide Dinitrate (ISDN)-from DrugReservoir

I. Patch Formula:

    ______________________________________                                        ISDN (50% on Latose)                                                                              15%                                                       PVC Resin           30%                                                       AZONE ®         32%                                                       Isopropyl Myristate 20%                                                       Aerosil (Fumed Silica)                                                                             3%                                                       ______________________________________                                    

II. Pharmacological Activity: Vasodilator

III. Test Protocol:

Formulations containing 7.5% ISDN, and 0, and 32% AZONE® respectivelywere tested in vivo on monkeys. Each formulation was tested on twomonkeys for six consecutive days. The patches were firmly placed on theshaved upper innerarm each morning and were left in place for eighthours. For each test condition blood samples of approximately 3-4 mlwere withdrawn from an indwelling catheter inserted into the saphenousvein. Blood samples were drawn at 0 (prior to patch application), 4 and8 hours after dosing. The eight-hour samples was drawn before thepatches were removed. The plasma component was immediately separatedfrom the blood by centrifugation at 1200 rpm for 5 minutes, and frozenat -20° C. The samples were then extracted to determine concentrationsof ISDN and its metabolites Isosorbide 5-mononitrate (5-ISMN) andIsosorbide 2-Mononitrate (2-ISMN).

Upon removal of the patches, the site of application was washed withdilute alcohol and inspected visually. Any changes in the condition ofthe skin (such as erythema or edema) was scored according to the DrazeScoring System. This inspection was repeated 30 minutes and again beforenext patch application.

IV. Results:

The mean plasma ISDN and metabolite results for the patches are shown inTable I. An increase of 300% to 400% in plasma ISDN concentration wasobserved for patches containing 32% AZONE®.

A maximum of 43.8% ng/ml of plasma ISDN was obtained from 2patches witha total surface area of 12.5 cm². However, the data did not suggest thatthere was a linear increase of plasma level with surface area of patch.In general, doubling the patch surface area more than doubled the plasmalevel, for ISDN as well as the metabolites.

                  TABLE I                                                         ______________________________________                                        8 HOURS IN VIVO RESULTS OF                                                    ISDN PATCHES ON MONKEYS                                                       AVERAGE CONCENTRATION (ng/ml)                                                 % AZONE ®                                                                           No. Patches*                                                                              ISDN    5 ISMN  2 ISMN                                  ______________________________________                                         0        1            3.46   12.75    3.05                                             2           19.39   55.52   12.67                                   12        1            6.08   23.56    4.64                                             2           30.23   68.43   17.11                                   32        1           14.14   42.01    9.75                                             2           43.85   87.85   23.75                                   ______________________________________                                         *Patch size was 6.25 cm.sup.2.                                           

What is claimed is:
 1. A device for the controlled release and deliveryto .[.human.]. tissue of a pharmacologically-active agent comprising asolid vinyl plastisol layer comprising by weight from about 30 up toabout 50% polyvinyl chloride resin; from about 20 up to about 70% ofplasticizer and from about 0.5 up to about 35% of saidpharmacologically-active substance which when a surface of said layer isin contact with a tissue either exterior to the human epidermis orsubdermally or in contact with a tissue of an animal to be treated withsaid pharmacologically-active agent, said pharmacologically-active agentis absorbed into and through said tissue and thence into circulatorysystem of said animal, said pharmacologically-active agent beinguniformly dispersed in said plastisol layer in an amount such that aneffective amount of said pharmacologically-active agent is absorbed intosaid animal in a prescribed period of time.
 2. The device of claimwherein .Iadd.at least one .Iaddend.control .[.membranes.]..Iadd.membrane .Iaddend.for secondary control of release .[.are.]..Iadd.is .Iaddend.attached on one or both sides of said device.
 3. Thedevice of claim 1 wherein the plasticizer is a polymeric plasticizer. 4.The device of claim 1 wherein the plasticizer is a monomericplasticizer.
 5. The .[.article.]. .Iadd.device .Iaddend.wherein theplasticizer is dioctyl phthalate.
 6. The .[.article.]. .Iadd.device.Iaddend.wherein the polymeric plasticizer is a polyphthalate.
 7. The.[.article.]. .Iadd.device .Iaddend.of claim 3 wherein the polymericplasticizer is epoxidized soybean oil.
 8. The .[.article.]. .Iadd.device.Iaddend.of claim 2 wherein the polyvinyl chloride is present in anamount of about 30-50%, the plasticizer is present in an amount of about30-60% and the pharmacologically-active agent is present in an amount ofabout 0.5-35%.
 9. The .[.article.]. .Iadd.device .Iaddend.of claim 1 inthe form of an elongated tape.
 10. The .[.article.]. .Iadd.device.Iaddend.of claim 9 wherein said plastisol layer comprises polyvinylchloride resin, a polymeric plasticizer or a monomeric plasticizer and apharmacologically-active agent selected from the group consisting ofisosorbide dinitrate, nicotine, indomethacin clonidine, glyercyltrinitrate, guanfacine and prostaglandin.
 11. The .[.article.]..Iadd.device .Iaddend.of claim 10 wherein said polyvinyl chloride ispresent in an amount of about 30-50%, said plasticizer is present in anamount of about 30-60% and said pharmacologically-active agent ispresent in an amount of from about 0.5 to about 35%.
 12. The.[.article.]. .Iadd.device .Iaddend.of claim 11 wherein thepharmacologically-active agent is nitroglycerin and the nitroglycerin ispresent in an amount of about 20-35%.
 13. The .[.article.]. .Iadd.device.Iaddend.of claim 11 wherein said tape is provided with indiciaindicating the length of a segment of said tape which is adequate toadminister a prescribed dosage of said pharmacologically-activesubstance.
 14. The .[.article.]. .Iadd.device .Iaddend.of claim 9 in theform of a roll of tape of sufficient length to provide multiple tapesegments adequate to provide a prescribed dosage of saidpharmacologically-active agent.
 15. A device for the controlled releaseand transdermal delivery of a pharmcologically-active agent comprising,a solid vinyl plastisol layer comprising by weight from about 30 up toabout 50% of a polyvinyl chloride resin; from about 20 up to about 70%of a plasticizer and from about 0.5 up to about 35% of apharmacologically-active agent which, when a surface of said layer is incontact with the skin of an animal to be treated with saidpharmacologically-active agent, is absorbed into and through skin andthence into the circulatory system of said animal, saidpharmacologically-active agent being uniformly dispersed in saidplastisol layer in an amount such that an effective amount of thepharmacologically-active agent is absorbed through the skin of saidanimal in a prescribed period of time, a backing layer covering thesurface of said plastisol layer opposite the skin contacting surface ofsaid plastisol layer, said backing layer forming a barrier substantiallyblocking release of said pharmacologically-active agent from the surfaceof said plastisol layer opposite the skin contacting surface, and meansfor maintaining the skin contacting surface of said plastisol layer incontact with the skin of said animal so that transdermal absorption ofsaid pharmacologically-active agent takes place.
 16. The device of claim15 wherein a rate controlling membrane is attached to the plastisollayer on the side of the plastisol layer opposite to the backing layer.17. .[.An article.]. .Iadd.The device .Iaddend.of claim 15 or 16 whereinthe means for maintaining the skin contacting surface of said plastisollayer in contact with the skin is a pressure sensitive adhesive adheredto the plastisol layer on the side of the plastisol layer opposite saidbacking layer.
 18. .[.An article.]. .Iadd.The device .Iaddend.of claim15 or 16 wherein the means for maintaining the skin contacting surfaceof said plastisol layer in contact with the skin is a pressure sensitiveadhesive layer adhered to the side of the backing layer opposite theplastisol layer and extending beyond the periphery of the plastisollayer.
 19. The device of claim 15 or 16 wherein said plasticizer is apolymeric plasticizer or a monomeric plasticizer.
 20. The .[.article.]..Iadd.device .Iaddend.of claim 19 wherein the polymeric plasticizer is apolyphthalate.[.having the IR spectrum of FIG. 12.]..
 21. The.[.article.]. device of claim 19 wherein the plasticizer is dioctylphthalate.
 22. The .[.article.]. device of claim 19 wherein thepolymeric plasticizer is epoxidized soybean oil.
 23. The device of claim15 or 16 wherein said polyvinyl chloride is present in an amount ofabout .Badd.30-50%, said plasticizer is present in an amount of about30-60, and said pharmacologically-active agent is present in an amountof about 0.5-35%.
 24. The device of claim 17 in the form of an elongatedtape.
 25. The device of claim 24 wherein the plasticizer is a polymericplasticizer.
 26. The device of claim 25 wherein said polyvinyl chlorideis present in an amount of about 30-50%, said plasticizer is present inan amount of about 30-60%, and said pharmacologically-active agent ispresent in am amount of about 0.5-35%.
 27. The device of claim 24wherein said tape is provided with indicia indicating the length of asegment of said tape which is adequate to administer a prescribed dosageof said pharmacologically-active agent.
 28. The device of claim 24 inthe form of a roll of tape of sufficient length to provide multiple tapesegments adequate to provide a prescribed dosage of said drug.
 29. The.[.article of manufacture.]. .Iadd.device .Iaddend.of claim 1 whereinthe plasticizer is the compound having the structure: ##STR27##
 30. The.[.article of manufacture.]. .Iadd.device .Iaddend.of claim 1 whereinthe plasticizer is N,N-diethyltoluaminde.
 31. The .[.article.]..Iadd.device .Iaddend.of claim 2 or 16 wherein the rate controllingmembrane comprises an ethylene-methyl acrylate copolymer having 2-90% byweight of methyl acrylate monomeric units. .Iadd.32. The device of claim11 wherein the pharmacologically-active agent is nitroglycerin and thenitroglycerin is present in an amount of about 8.0-10%. .Iaddend..Iadd.33. The device of claim 3 wherein the polyermic plasticizer is apolyadipate. .Iaddend. .Iadd.34. The device of claim 19 wherein thepolymeric plastizicer is a polyadipate. .Iaddend.